DESCRIPTION: Applicant's Abstract There has been little study of biologic factors which influence drug addiction in women. Recent studies suggest that women may be more sensitive to some effects of locomotor stimulants like cocaine. The purpose of the present proposal is to investigate possible biologic factors which might lead to differential effects of stimulants in males and females. Our previous studies have documented a robust gender difference in the locomotor response to cocaine in rats that is accompanied by markedly enhanced dopamine release as assessed with fast-scan cyclic voltammetry (FSCV) in intact brain and brain slices. The goal of the present proposal is to test the hypothesis that the integration of rapid membrane effects of estrogen on dopamine release and slow effects on dopamine transporter synthesis mediate the greater response of female rats to the locomotor stimulant actions of cocaine and the enhanced dopamine release that females demonstrate relative to males. To test this hypothesis, we plan to compare the ability of estrogen (E), progesterone (P), E+P or testosterone (T) receptors to influence locomotor responses to cocaine and dopamine release in ovariectomized (OVX) or castrated (CAS) rats, using dose response, time course and pharmacologic specificity studies of hormone effects. Dopamine uptake and release will be assessed using in vivo and in vitro FSCV. The last specific aim will address the related hypothesis that these effects of E, P or T are indirect, and mediated through central actions of CRF and/or corticosterone. These studies should provide insight into basic mechanisms which mediate gender differences in dopaminergic function and the effects of locomotor stimulants which depend upon dopaminergic transmission.